The overall goal is to identify the gene (dn) that is defective in the deafness (dn/dn) mouse. The applicants have mapped the dn gene to mouse chromosome 19 and it is likely to be the ortholog of the human DFNB7/11 gene on chromosome 9q13-q21. The deafness mouse is an autosomal recessive mutant of the curly-tail (CT) stock showing degeneration of the organ of Corti, stria vascularis, and the saccular macula. Ultrastructural abnormalities of the inner hair cells have been shown to be present at birth, and by 15-20 days after birth there are abnormalities of the extracellular spaces of the organ of Corti as well as loss of inner and outer hair cells. By 45 days after birth the inner and outer hair cells have degenerated completely, and the organ of Corti has no distinguishable cell types from base to apex. Interestingly, regeneration of cells other than hair cells occurs in the apical turn between 45 and 90 days after birth. Unlike other mouse models for deafness, the dn/dn mouse does not exhibit circling behavior, indicative of vestibular dysfunction, and therefore may provide insight into the auditory system as distinct from the vestibular system. Preliminary linkage and physical mapping data suggest that the deafness phenotype is associated with a chromosomal rearrangement, probably an inversion. Based on these results, the applicants propose to identify both breakpoints of the inversion, identify and characterize candidate genes, and create a hearing dn/dn mouse using transgenic technology. The specific aims are to: (1) Isolate and determine the sequence at both inversion breakpoints; (2) Identify candidate genes in the vicinity of the chromosomal rearrangement; (3) Isolate cDNAs and analyze for abnormal expression and gene structure in the dn/dn mouse relative to the +/+ mouse; and (4) Rescue the deafness phenotype via the transfer of BAC DNA directly into dn/dn mouse embryos. The deafness mouse is a model for nonsyndromic profound hearing impairment, and identifying the defective gene will be a valuable contribution to our understanding of the genes needed for normal cochlear function.